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Andersen, Peter
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Publications (10 of 110) Show all publications
Nordin, A., Akimoto, C., Wuolikainen, A., Alstermark, H., Jonsson, P., Birve, A., . . . Andersen, P. M. (2015). Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD. Human Molecular Genetics, 24(11), 3133-3142
Open this publication in new window or tab >>Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD
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2015 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 11, p. 3133-3142Article in journal (Refereed) Published
Abstract [en]

A GGGGCC-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among Caucasians. However, little is known about the variability of the GGGGCC expansion in different tissues and whether this correlates with the observed phenotype. Here, we used Southern blotting to estimate the size of hexanucleotide expansions in C9orf72 in neural and non-neural tissues from 18 autopsied ALS and FTD patients with repeat expansion in blood. Digitalization of the Southern blot images allowed comparison of repeat number, smear distribution and expansion band intensity between tissues and between patients. We found marked intra-individual variation of repeat number between tissues, whereas there was less variation within each tissue group. In two patients, the size variation between tissues was extreme, with repeat numbers below 100 in all studied non-neural tissues, whereas expansions in neural tissues were 20-40 times greater and in the same size range observed in neural tissues of the other 16 patients. The expansion pattern in different tissues could not distinguish between diagnostic groups and no correlation was found between expansion size in frontal lobe and occurrence of cognitive impairment. In ALS patients, a less number of repeats in the cerebellum and parietal lobe correlated with earlier age of onset and a larger number of repeats in the parietal lobe correlated with a more rapid progression. In 43 other individuals without repeat expansion in blood, we find that repeat sizes up to 15 are stable, as no size variation between blood, brain and spinal cord was found.

National Category
Medical Genetics Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-103256 (URN)10.1093/hmg/ddv064 (DOI)000355674000011 ()25712133 (PubMedID)
Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2018-01-11Bibliographically approved
Freischmidt, A., Wieland, T., Richter, B., Ruf, W., Schaeffer, V., Mueller, K., . . . Weishaupt, J. H. (2015). Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nature Neuroscience, 18(5), 631-+
Open this publication in new window or tab >>Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
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2015 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 18, no 5, p. 631-+Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-103728 (URN)10.1038/nn.4000 (DOI)000353636900009 ()25803835 (PubMedID)
Available from: 2015-06-09 Created: 2015-05-28 Last updated: 2018-01-11Bibliographically approved
Bergh, J., Zetterström, P., Andersen, P. M., Brännström, T., Graffmo, K. S., Jonsson, P. A., . . . Marklund, S. (2015). Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping. Proceedings of the National Academy of Sciences of the United States of America, 112(14), 4489-4494
Open this publication in new window or tab >>Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping
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2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 14, p. 4489-4494Article in journal (Refereed) Published
Abstract [en]

Despite considerable progress in uncovering the molecular details of protein aggregation in vitro, the cause and mechanism of protein-aggregation disease remain poorly understood. One reason is that the amount of pathological aggregates in neural tissue is exceedingly low, precluding examination by conventional approaches. We present here a method for determination of the structure and quantity of aggregates in small tissue samples, circumventing the above problem. The method is based on binary epitope mapping using anti-peptide antibodies. We assessed the usefulness and versatility of the method in mice modeling the neurodegenerative disease amyotrophic lateral sclerosis, which accumulate intracellular aggregates of superoxide dismutase-1. Two strains of aggregates were identified with different structural architectures, molecular properties, and growth kinetics. Both were different from superoxide dismutase-1 aggregates generated in vitro under a variety of conditions. The strains, which seem kinetically under fragmentation control, are associated with different disease progressions, complying with and adding detail to the growing evidence that seeding, infectivity, and strain dependence are unifying principles of neurodegenerative disease.

Place, publisher, year, edition, pages
National Academy of Sciences, 2015
Keyword
protein aggregation, neurodegeneration, strain, amyotrophic lateral sclerosis, transgenic mice
National Category
Pharmacology and Toxicology Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-103147 (URN)10.1073/pnas.1419228112 (DOI)000352287800075 ()25802384 (PubMedID)
Available from: 2015-05-28 Created: 2015-05-18 Last updated: 2018-01-11Bibliographically approved
Akimoto, C., Volk, A. E., van Blitterswijk, M., Van den Broeck, M., Leblond, C. S., Lumbroso, S., . . . Kubisch, C. (2014). A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories. Journal of Medical Genetics, 51(6), 419-424
Open this publication in new window or tab >>A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories
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2014 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, no 6, p. 419-424Article in journal (Refereed) Published
Abstract [en]

Background The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories. Methods The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference. Results Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories. Conclusions Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.

National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-91059 (URN)10.1136/jmedgenet-2014-102360 (DOI)000336841300009 ()
Available from: 2014-07-11 Created: 2014-07-10 Last updated: 2018-01-11Bibliographically approved
Fogh, I., Ratti, A., Gellera, C., Lin, K., Tiloca, C., Moskvina, V., . . . Silani, V. (2014). A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Human Molecular Genetics, 23(8), 2220-2231
Open this publication in new window or tab >>A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis
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2014 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 8, p. 2220-2231Article in journal (Refereed) Published
Abstract [en]

Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (90) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P 1.11 10(8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P 8.62 10(9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P 7.69 10(9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as 12 using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

Place, publisher, year, edition, pages
Oxford: Oxford University Press, 2014
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-87867 (URN)10.1093/hmg/ddt587 (DOI)000333269400022 ()
Available from: 2014-04-15 Created: 2014-04-14 Last updated: 2017-12-05Bibliographically approved
Van Doormaal, P. T. C., Ticozzi, N., Gellera, C., Ratti, A., Taroni, F., Chio, A., . . . Veldink, J. H. (2014). Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study. Neurobiology of Aging, 35(10), 2420.e13
Open this publication in new window or tab >>Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study
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2014 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 35, no 10, p. 2420.e13-Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Elsevier, 2014
Keyword
Amyotrophic lateral sclerosis, Kinesin-associated protein 3 gene, KIFAP3, Genome-wide association study
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-92895 (URN)10.1016/j.neurobiolaging.2014.04.014 (DOI)000339735100031 ()
Available from: 2014-09-18 Created: 2014-09-09 Last updated: 2017-12-05Bibliographically approved
Bergström, P., von Otter, M., Nilsson, S., Nilsson, A.-C., Nilsson, M., Andersen, P., . . . Zetterberg, H. (2014). Association of NFE2L2 and KEAP1 haplotypes with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 15(1-2), 130-137
Open this publication in new window or tab >>Association of NFE2L2 and KEAP1 haplotypes with amyotrophic lateral sclerosis
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2014 (English)In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, Vol. 15, no 1-2, p. 130-137Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron syndrome influenced by oxidative stress. The transcription factor Nrf2 and its repressor Keap1 constitute an important defence system in cellular protection against oxidative stress. Here we hypothesize that common genetic variations in the genes NFE2L2 and KEAP1, encoding Nrf2 and Keap1, may influence the risk and phenotype of ALS. Five hundred and twenty-two Swedish patients with sporadic ALS (SALS) and 564 Swedish control subjects were studied. Eight tag SNPs in NFE2L2 and three tag SNPs in KEAP1 were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. One NFE2L2 haplotype (GGGAC) was associated with decreased risk of SALS (OR = 0.62 per allele, p = 0.003) and one haplotype in KEAP1 (CGG) was associated with later SALS onset (+3.4 years per allele, p = 0.015). When stratified by subgroup, one haplotype in NFE2L2, GAGCAGA including three functional promoter SNPs associated with high Nrf2 protein expression, was associated with 4.0 years later disease onset per allele in subgroup ALS (p = 0.008). In conclusion, these results suggest that variations in NFE2L2 and KEAP1, encoding two central proteins in cellular oxidative stress defence, may influence SALS pathogenesis.

Place, publisher, year, edition, pages
Informa Healthcare, 2014
Keyword
Amyotrophic lateral sclerosis, ALS, Nrf2, NFE2L2, KEAP1, SNP, haplotype, risk factor
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-87634 (URN)10.3109/21678421.2013.839708 (DOI)000332417000018 ()
Available from: 2014-04-10 Created: 2014-04-07 Last updated: 2018-01-11Bibliographically approved
Diekstra, F. P., Van Deerlin, V. M., van Swieten, J. C., Al-Chalabi, A., Ludolph, A. C., Weishaupt, J. H., . . . Veldink, J. H. (2014). C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Genome-Wide Meta-Analysis. Annals of Neurology, 76(1), 120-133
Open this publication in new window or tab >>C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Genome-Wide Meta-Analysis
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2014 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 76, no 1, p. 120-133Article in journal (Refereed) Published
Abstract [en]

Objective: Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods: We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 x 10(-12)) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 x 10(-11)) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 x 10(-7)) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 x 10(-7)). Interpretation: We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.

Place, publisher, year, edition, pages
John Wiley & Sons, 2014
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-92950 (URN)10.1002/ana.24198 (DOI)000340043200012 ()
Available from: 2014-09-16 Created: 2014-09-09 Last updated: 2017-12-05Bibliographically approved
Rosenbohm, A., Kassubek, J., Weydt, P., Marroquin, N., Volk, A. E., Kubisch, C., . . . Ludolph, A. C. (2014). Can lesions to the motor cortex induce amyotrophic lateral sclerosis?. Journal of Neurology, 261(2), 283-290
Open this publication in new window or tab >>Can lesions to the motor cortex induce amyotrophic lateral sclerosis?
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2014 (English)In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 261, no 2, p. 283-290Article in journal (Refereed) Published
Abstract [en]

A recent staging effort for amyotrophic lateral sclerosis (ALS) has demonstrated that the TDP-43 neuropathology may initiate focally in the motor cortex in the majority of patients. We searched our data bank for patients with lesions of the motor cortex which preceded disease onset. We performed a search of our patient- and MRI-data bank and screened 1,835 patients with amyotrophic lateral sclerosis for frontal lobe/motor cortex lesions. We found 18 patients with definite ALS who had documented and defined lesions of the motor cortex, which preceded the initial ALS symptoms by 8-42 years. In the vast majority (15/18) of the patients, the onset of ALS was closely related to the focal lesion since it started in a body region reflecting the damaged cortical area. The findings suggest that initial lesions to the motor cortex may be a contributing initiating factor in some patients with ALS or determine the site of onset in individuals pre-disposed to ALS.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-87173 (URN)10.1007/s00415-013-7185-7 (DOI)000330963200005 ()
Available from: 2014-03-31 Created: 2014-03-24 Last updated: 2018-01-11Bibliographically approved
Wuolikainen, A., Acimovic, J., Loevgren-Sandblom, A., Parini, P., Andersen, P. M. & Bjoerkhem, I. (2014). Cholesterol, Oxysterol, Triglyceride, and Coenzyme Q Homeostasis in ALS. Evidence against the Hypothesis That Elevated 27-Hydroxycholesterol Is a Pathogenic Factor. PLoS ONE, 9(11), e113619
Open this publication in new window or tab >>Cholesterol, Oxysterol, Triglyceride, and Coenzyme Q Homeostasis in ALS. Evidence against the Hypothesis That Elevated 27-Hydroxycholesterol Is a Pathogenic Factor
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e113619-Article in journal (Refereed) Published
Abstract [en]

High plasma levels of cholesterol have been suggested to be neuroprotective for the degenerative disease amyotrophic lateral sclerosis (ALS) and to be associated with increased survival time. The gene encoding cholesterol 27-hydroxylase, CYP27A1, was recently identified as a susceptibility gene for sporadic ALS. A product of this enzyme is 27-hydroxycholesterol. We investigated plasma samples from 52 ALS patients and 40 control subjects (spouses) regarding cholesterol homeostasis, lipid profiles, and coenzyme Q. Eleven of the patients carried mutations in C9orf72 and seven in SOD1. Plasma levels of 27-hydroxycholesterol were significantly lower in male patients with ALS than in controls. It was not possible to link the reduced levels to any specific mutation, and there was no significant correlation between 27-hydroxycholesterol and survival. With normalization for diet using the spouses, a correlation was found between survival and total cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, and coenzyme Q. We conclude that cholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol and lipid profiles in plasma are of limited prognostic value in individual ALS patients.

National Category
Neurosciences Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-99386 (URN)10.1371/journal.pone.0113619 (DOI)000346906600065 ()
Available from: 2015-02-27 Created: 2015-02-07 Last updated: 2018-01-11Bibliographically approved
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